Long-Term Cardiovascular outcomes Differ Across Metabolic Dysfunction-Associated Fatty Liver Disease Subtypes

Abstract Background & Aims: The new metabolic dysfunction-associated fatty liver disease (MAFLD) criteria include three distinct subtypes: MAFLD with diabetes mellitus (DM), overweight/obese (OW), or lean/normal weight with metabolic dysfunction. We investigated whether long-term cardiovascular disease outcomes differ across the MAFLD subtypes.Methods: From a nationwide health screening database, we included 8,412,730 participants (48.6% male) aged 40-64 years, free of cardiovascular disease history, between 2009 and 2010. Participants were categorized into non-MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. The primary outcome was a composite cardiovascular disease event, including myocardial infarction, ischemic stroke, heart failure, or cardiovascular disease-related death. The presence of advanced liver fibrosis was estimated using a BARD score ≥2. Results: Among the study participants, 3,087,640 (36.7%) had MAFLD, among which 2,424,086 (78.5%), 170,761 (5.5%), and 492,793 (16.0%) had OW-MAFLD, lean-MAFLD, and DM-MAFLD, respectively. Over a median follow-up period of 10.0 years, 169,433 new cardiovascular disease events occurred. With the non-MAFLD group as reference, multivariable-adjusted hazard ratios (95% confidence intervals) for cardiovascular disease events were 1.16 (1.15-1.18), 1.23 (1.20-1.27), and 1.82 (1.80-1.85) in the OW-MAFLD, lean-MAFLD, and DM-MAFLD groups, respectively. Participants with lean-MAFLD or DM-MAFLD had a higher cardiovascular disease risk than those with OW-MAFLD, irrespective of metabolic abnormalities or comorbidities. The presence of advanced liver fibrosis was significantly associated with a higher cardiovascular disease risk in each MAFLD subtype.Conclusion: Long-term cardiovascular disease outcomes differed across the MAFLD subtypes. Further studies are required to investigate whether preventive or therapeutic interventions should be optimized according to the MAFLD subtypes.